Peptide-Modified Gemini Surfactants as Delivery System Building Blocks with Dual Functionalities for Glaucoma Treatment: Gene Carriers and Amyloid-Beta (A beta) Self-Aggregation Inhibitors

ABSTRACT: Retinal ganglion cell (RGC) neurodegeneration in glaucoma has potential links with amyloid-fi (Afi) deposition. Targeting the Afi pathway was shown to reduce RGC apoptosis and protect RGCs from degeneration. We report exploratory studies on the amyloid Afi40 aggregation inhibition properties of four cell adhesion peptide (CAP)-gemini surfactants that are intended as building blocks for gene carrier nanoparticles for glaucoma treatment. The CAP-gemini surfactants (18-7N(p1-4)-18) were evaluated as potential Afi40 peptide aggregation inhibitors by a fluorescence kinetic assay and for their binding interactions with Afi40 dimers by molecular docking studies. In vitro Afi40 peptide aggregation inhibition studies showed that the 18-7N(p3)-18 and 18-7N(p1)-18 ligands inhibit Afi40 peptide aggregation and prevent the formation of higher order structures. CDOCKER energies and CDOCKER interaction energies demonstrated that the CAP-gemini surfactants formed more stable complexes in the Afi40 dimer assembly and underwent both polar and nonpolar interactions compared to CAP peptides alone. Also, 18-7N(p3)-18 showed a significantly lower CDOCKER energy compared to that of the unmodified gemini surfactant 18-7NH-18 (p < 0.0001) and 18-7N(p4)-18 (p < 0.001), 18-7N(p1)-18, and 18-7N(p2)-18. Similarly, 18-7N(p3)-18 showed a significantly lower CDOCKER interaction energy compared to that of 18-7NH-18, 18-7N(p4)-18 (p < 0.0001), and 18-7N(p2)-18 (p < 0.001), while 18-7N(p3)-18 and 18-7N(p1)-18 showed similar CDOCKER interaction energies. These studies suggest that a combination of both hydrophobic and electrostatic interactions contributes to the anti-Afi40 aggregation activity of CAP-gemini surfactants. CAP-gemini surfactants showed 10-fold better Afi40 peptide aggregation inhibition compared to previously reported values and could provide a new opportunity for glaucoma treatment as dual-functional gene carriers.